Methionine has been shown to increase plasma cholesterol in animals. In the present study, mechanisms were investigated by which methionine could alter cholesterol metabolism. In the first experiment, forty growing rats were fed four casein-based diets differing in methionine content (2·6, 3·5, 4·5 or 6·0 g/kg) for 14 d. In the second experiment, isolated rat hepatocytes were incubated in media supplemented with 50, 100 or 200 mmol/l methionine. Dietary methionine tended to increase plasma homocysteine concentrations in the rats (P¼0·058). A weak positive correlation between circulating homocysteine and plasma cholesterol was observed (R 2 0·27, P,0·01). Rats fed 3·5 g/kg or more of methionine had higher concentrations of cholesterol in their plasma, in lipoprotein fractions of density (r; kg/l) 1·006 , r , 1·063 and r . 1·063, and in liver than rats fed 2·6 g/kg methionine. Rats fed 6 g/kg methionine had a higher hepatic expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol-7a-hydroxylase than rats fed less methionine. The phosphatidylcholine:phosphatidylethanolamine ratio in rat liver increased with rising dietary methionine concentration; the relative mRNA concentrations of phosphatidylethanolamine N-methyltransferase and cystathionine b-synthase remained unaffected. Hepatocytes incubated in media supplemented with 100 or 200 mmol/l methionine had a higher cholesterol synthesis than hepatocytes incubated in a medium supplemented with 50 mmol/l methionine; the LDL uptake in hepatocytes was independent of the methionine concentration of the medium. In conclusion, the present study suggests that dietary methionine induces hypercholesterolaemia at least in part via an enhanced hepatic cholesterol synthesis. Previous studies on the effects of dietary proteins on plasma cholesterol have shown that casein raises serum and LDL-cholesterol concentration in animals and man, whereas plant proteins such as soya protein do not (Ikeda et al.

Background and Aims: Dietary methionine affects cholesterol metabolism in growing rats. Methionine effects on adult rats and mechanisms by which methionine alters the lipid metabolism are not fully elucidated. We investigated possible mechanisms by which dietary methionine acts on lipid metabolism of adult rats. Methods: Male adult rats were divided into three groups (n = 10) and were fed casein-based diets differing in methionine concentration (low-methionine diet: 0.96 g/kg; adequate-methionine diet: 2.22 g/kg, high-methionine diet: 6.82 g/kg) for 4 weeks. Concentrations of triacylglycerols and cholesterol in plasma and lipoproteins, concentration of homocysteine in plasma, concentration of cholesterol in liver, fecal lipid excretion, expression of hepatic HMG-CoA reductase, phosphatidylethanolamine N-methyltransferase 2 (PEMT-2) and of LDL receptor were measured. Results: Rats fed the high-methionine diet had higher plasma homocysteine concentrations than rats fed the low-methionine diet (p < 0.05). Although concentrations of cholesterol in plasma and lipoproteins were not different between the groups, there was a distinct positive correlation between circulating plasma homocysteine and plasma cholesterol (R² = 0.55, p < 0.001). The fecal excretion of cholesterol and bile acids was not altered by dietary methionine. The relative mRNA concentration of HMG-CoA reductase and of LDL receptor remained unaffected by dietary methionine. Gene expression of PEMT-2 was higher in rats fed the high-methionine diet than in rats fed the other diets (p < 0.05). Conclusion: The results demonstrate that dietary methionine contributes to a rise in circulating homocysteine concentration which positively correlates with the concentration of plasma cholesterol. However, the effects of methionine on cholesterol metabolism of adult rats were relatively weak.